There is described in U.S. Pat. Nos. 4,536,518 and 4,556,676 to W. M. Welch, Jr. et al., as well as in the paper of W. M. Welch, Jr. et al., appearing in the Journal of Medicinal Chemistry, Vol. 27, No. 11, p. 1508 (1984), a multi-step method for synthesizing pure racemic cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthal eneamine, starting from the readily available 3,4-dichlorobenzophenone. In the last step of this synthesis, N-[4 -(3,4 -dichlorophenyl) -3,4-dihydro-1(2H) -naphthalenylidene]methenamine is reduced by means of catalytic hydrogenation or by the use of a metal hydride complex to N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine, which is actually a mixture of the cis- and trans-isomers in the form of a racemate. The aforesaid isomeric mixture is then separated into its component parts by conventional means, e.g., by fractional crystallization of the hydrochloride salts or by column chromatography on silica gel of the corresponding free base. Resolution of the separated cis- racemate free base compound while in solution with an optically-active selective precipitant acid, such as D-(-)-mandelic acid, in a classical manner then ultimately affords the desired cis-(1S)(4S)-enantiomer (sertraline).
Nevertheless, the above described production of pure cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro- 1-naphthaleneamine is disadvantageous in that large amounts of the unwanted racemic trans-isomer (which ultimately leads to the unwanted trans-(1S)(4R)-enantiomer) are co-produced and must eventually be discarded, thereby lowering the overall yield of the desired cis-(1S)(4S)-enantiomer and increasing the costs of production. Therefore, it is an object of the present invention to utilize the unwanted trans-isomer that is co-produced in the aforesaid synthesis and so lower the total costs of production. Another and more specific object of the present invention is to convert the aforesaid trans-racemate free base to the corresponding cis-isomer and thereby, in effect, recycle the previously unwanted trans-isomer back into the present method of production for the desired cis-isomer. Still another and even more specific object of the present invention is to convert the previously unwanted chiral trans-(1S)(4R)-isomer into the corresponding chiral cis-(1S)(4S)-isomer which is, of course, sertraline.